Pyrin Inflammasome Activation Defines Colchicine-Responsive SURF Patients from FMF and Other Recurrent Fevers.

Syndrome of undifferentiated recurrent fever (SURF) is characterized by recurrent fevers, a lack of confirmed molecular diagnosis, and a complete or partial response to colchicine. Despite the clinical similarities to familial Mediterranean fever (FMF), the underlying inflammatory mechanisms of SURF are not yet understood. We here analyzed the in vitro activation of the pyrin inflammasome in a cohort of SURF patients compared to FMF and PFAPA patients. Peripheral blood mononuclear cells (PBMC) were collected from SURF (both colchicine-treated and untreated), FMF, PFAPA patients, and healthy donors. PBMC were stimulated ex vivo with Clostridium difficile toxin A (TcdA) and a PKC inhibitor (UCN-01), in the presence or absence of colchicine. The assembly of the pyrin inflammasome was evaluated by measuring the presence of apoptosis-associated Speck-like protein containing caspase recruitment domain (ASC) specks in monocytes using flow cytometry. IL-1ß secretion was quantified using an ELISA assay. No differences in TcdA-induced activation of pyrin inflammasome were observed among FMF, PFAPA, and healthy donors. Untreated SURF patients showed a reduced response to TcdA, which was normalized after colchicine treatment. In contrast to FMF, SURF patients, similar to PFAPA patients and healthy donors, did not exhibit pyrin inflammasome activation in response to UCN-01-mediated pyrin dephosphorylation. These data demonstrate that in vitro functional analysis of pyrin inflammasome activation can differentiate SURF from FMF and PFAPA patients, suggesting the involvement of the pyrin inflammasome in the pathophysiology of SURF.

Efficacy and safety of anti-interleukin-1 treatment in familial Mediterranean fever patients: a systematic review and meta-analysis.

OBJECTIVES: FMF is the most common hereditary monogenic fever syndrome marked by recurrent attacks of fever and polyserositis. Colchicine is the current recommended first-line treatment for FMF. However, a small portion of FMF patients are unresponsive or intolerant to colchicine. Anti-IL-1 agents are alternative treatment options for colchicine-resistant or -intolerant FMF patients. This systematic review and meta-analysis aimed to provide qualitative and quantitative evidence for the efficacy and safety of anti-IL-1 agents in adult and paediatric FMF patients. METHODS: MEDLINE, EMBASE, CENTRAL and Web of Science were screened from inception to May 2023. We included adult and paediatric FMF patients who received continuous treatment with at least one of the anti-IL-1 drugs: anakinra, canakinumab and rilonacept. The primary efficacy outcome was the proportion of patients who achieved complete remission of attacks and the primary safety outcome was the proportion of patients who experienced at least one adverse event during treatment. A random-effects meta-analysis was performed for the quantitative synthesis. RESULTS: Fourty-four reports consisting of 1399 FMF patients were included. Sixty percent (95% CI 49%, 72%) of the adult patients and 81% (95% CI 72%, 89%) of the paediatric patients achieved complete remission. Anti-IL-1 agents significantly decreased levels of inflammatory markers. At least one adverse event was observed in 25% (95% CI 13%, 37%) of the adult patients and 12% (95% CI 3%, 21%) of the paediatric patients. CONCLUSION: Anti-IL-1 agents were effective and demonstrated a low adverse event profile in paediatric and adult FMF patients.

Pregnancy outcomes in patients with familial Mediterranean fever: systematic review and meta-analysis.

OBJECTIVE: The relationship between FMF and pregnancy outcomes remains unclear. This systematic review and meta-analysis aimed to clarify this association. METHODS: Electronic databases-PubMed, Web of Science, Cochrane, and EMBASE-were searched on 20 December 2022, using specific search terms. Case-control, cohort, and randomized clinical trial studies comparing patients with FMF and healthy controls were considered eligible. We excluded systematic reviews, meta-analyses, case series with fewer than five cases, republished articles without new findings on pregnancy outcomes, studies targeting paternal FMF, and those not published in English. The results were summarized in the form of odds ratios (ORs) and 95% CIs, using a random-effects model. This study was registered in the University hospital Medical Information Network Clinical Trials Registry (Japan) as UMIN000049827. RESULTS: The initial electronic search identified 611 records, of which 9 were included in this meta-analysis (177 735 pregnancies, 1242 with FMF, and 176 493 healthy controls). FMF was significantly associated with increased odds of preterm deliveries (OR, 1.67; 95% CI, 1.05-2.67; I2 = 22%) and insignificantly associated with increased odds of fetal growth restriction (OR, 1.45; 95% CI, 0.90-2.34; I2 = 0%) and hypertensive disorders during pregnancy (OR, 1.28; 95% CI, 0.87-1.87; I2 = 0%). CONCLUSION: FMF was significantly associated with preterm delivery and insignificantly associated with fetal growth restriction and hypertensive disorders. All of the included studies were observational studies. Treatment characteristics were not fully collected from the articles, and further analysis of treatments for FMF in pregnancy is still warranted.

Gut microbiota alterations are associated with phenotype and genotype in familial Mediterranean fever.

OBJECTIVE: FMF is the most common monogenic autoinflammatory disease associated with MEFV mutations. Disease phenotype and response to treatment vary from one patient to another, despite similar genotype, suggesting the role of environmental factors. The objective of this study was to analyse the gut microbiota of a large cohort of FMF patients in relation to disease characteristics. METHODS: The gut microbiotas of 119 FMF patients and 61 healthy controls were analysed using 16 s rRNA gene sequencing. Associations between bacterial taxa, clinical characteristics, and genotypes were evaluated using multivariable association with linear models (MaAslin2), adjusting on age, sex, genotype, presence of AA amyloidosis (n = 17), hepatopathy (n = 5), colchicine intake, colchicine resistance (n = 27), use of biotherapy (n = 10), CRP levels, and number of daily faeces. Bacterial network structures were also analysed. RESULTS: The gut microbiotas of FMF patients differ from those of controls in having increased pro-inflammatory bacteria, such as the Enterobacter, Klebsiella and Ruminococcus gnavus group. Disease characteristics and resistance to colchicine correlated with homozygous mutations and were associated with specific microbiota alteration. Colchicine treatment was associated with the expansion of anti-inflammatory taxa such as Faecalibacterium and Roseburia, while FMF severity was associated with expansion of the Ruminococcus gnavus group and Paracoccus. Colchicine-resistant patients exhibited an alteration of the bacterial network structure, with decreased intertaxa connectivity. CONCLUSION: The gut microbiota of FMF patients correlates with disease characteristics and severity, with an increase in pro-inflammatory taxa in the most severe patients. This suggests a specific role for the gut microbiota in shaping FMF outcomes and response to treatment.

Colchicine: the good, the bad, the ugly and how to minimize the risks.

Colchicine has an important role in managing various conditions, including gout, familial Mediterranean fever, amyloidosis, Behçet's syndrome, recurrent pericarditis and calcium pyrophosphate deposition disease. The adverse effect profile of colchicine is well understood. However, due to its narrow therapeutic index, colchicine has been associated with overdose and fatalities. When ingested in toxic amounts, the mainstay of management is supportive care. Strategies to minimize the risk of colchicine poisoning can focus on three broad causes: unauthorized access, intentional overdose and inappropriate dosing. Culturally safe and appropriate education about storage and appropriate use of colchicine is essential to minimize the risk of overdose.

A score for predicting colchicine resistance at the time of diagnosis in familial Mediterranean fever: data from the TURPAID registry.

OBJECTIVES: Colchicine forms the mainstay of treatment in FMF. Approximately 5-10% of FMF patients are colchicine resistant and require anti-IL-1 drugs. We aimed to compare the characteristics of colchicine-resistant and colchicine-responsive patients and to develop a score for predicting colchicine resistance at the time of FMF diagnosis. METHODS: FMF patients (0-18 years) enrolled in the Turkish Paediatric Autoinflammatory Diseases (TURPAID) registry were included. The predictive score for colchicine resistance was developed by using univariate/multivariate regression and receiver operating characteristics analyses. RESULTS: A total of 3445 FMF patients [256 (7.4%) colchicine-resistant and 3189 colchicine-responsive) were included (female:male ratio 1.02; median age at diagnosis 67.4 months). Colchicine-resistant patients had longer, more frequent attacks and were younger at symptom onset and diagnosis (P < 0.05). Fever, erysipelas-like erythema, arthralgia, arthritis, myalgia, abdominal pain, diarrhoea, chest pain, comorbidities, parental consanguinity and homozygosity/compound heterozygosity for exon 10 MEFV mutations were significantly more prevalent among colchicine-resistant than colchicine-responsive patients (P < 0.05). Multivariate logistic regression analysis in the training cohort (n = 2684) showed that age at symptom onset, attack frequency, arthritis, chest pain and having two exon 10 mutations were the strongest predictors of colchicine resistance. The score including these items had a sensitivity of 81.3% and a specificity of 49.1%. In the validation cohort (n = 671), its sensitivity was 93.5% and specificity was 53.8%. CONCLUSION: We developed a clinician-friendly and practical predictive score that could help us identify FMF patients with a greater risk of colchicine resistance and tailor disease management individually at the time of diagnosis.

Old paradigms and new concepts in familial Mediterranean fever (FMF): an update 2023.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent attacks of fever and polyserositis. Its first description as a new entity was published by Siegal in 1945. Colchicine has been the treatment of choice for this disease since 1972. Significant progress has been made over the years in understanding FMF's clinical features, diagnosis, mode of inheritance, pathogenesis and therapeutic approach. However, many old paradigms related to FMF have proven inaccurate, leading to the emergence of new concepts that provide more precise insights. The term 'FMF' is no longer appropriate as the disease is found beyond the Mediterranean basin. The concept of diagnosis based only upon clinical ground proved to be wrong. The paradigm that MEFV mutations in FMF lead to loss of function of the encoded peptide pyrin turned out to be a gain of function mutation. Finally, the concept that as a genetic disease FMF should be treated for life was found to be inaccurate for the subpopulation of the heterozygote patients. Thus, the breakthroughs of identifying the gene associated with the disease (MEFV) and the deciphering of its pathogenesis revolutionized our old paradigms and replaced them with new and more precise insights.

Evaluation of the Inflammatory Response After Eradication of Helicobacter pylori in Patients With Familial Mediterranean Fever.

PURPOSE: Evaluation of the inflammatory response after Helicobacter pylori (Hp) eradication in patients with Familial Mediterranean Fever (FMF) during the non-attack period and determining whether there is a change in the ongoing inflammation during the non-attack period. MATERIALS AND METHODS: Sixty-four patients, who have not been eradicated for Hp in the last 2 years, diagnosed with FMF, and evaluated in the non-attack period, were included in the study. Hp eradication therapy was administered to patients who were found to be Hp-positive. C-reactive protein (CRP), high-sensitive C-reactive protein (hs-CRP), interleukin-6, interleukin-8, tumor necrosis factor-alpha, and serum amyloid A values were compared between the groups before and after eradication. RESULTS: CRP and hs-CRP levels were found to be statistically higher in the FMF group than in the control group. A statistically significant decrease was found in the values of CRP and hs-CRP, in the number of patients with attacks, and in attack frequency after eradication in the Infected Patients compared to the values before eradication. CONCLUSIONS: We determined a decrease in CRP and hs-CRP values, the number of patients with attacks, and attack frequency with the eradication of Infected Patients. In patients with FMF, in whom it has been proven by different studies that the inflammation continues during the non-attack period, it may be recommended to investigate the presence of Hp infection, which is thought to contribute to this inflammation and to give Hp eradication therapy to patients who are found positive to reduce the development of secondary complications caused by chronic inflammation.

The Influence of Coexisting Familial Mediterranean Fever on Crohn's Disease: Data From an FMF Endemic Area.

GOAL: The goal of this study was to evaluate the impact of coexisting familial Mediterranean fever (FMF) on Crohn's disease (CD) patients' phenotype and disease course in an endemic region for FMF. BACKGROUND: CD and FMF are inflammatory diseases characterized by recurrent abdominal pain and fever attacks. The impact of coexisting FMF on CD patients' phenotype and disease course is currently unknown. MATERIALS AND METHODS: We reviewed the medical records of 210 adult CD patients who were regularly followed up at a tertiary gastroenterology clinic between November 2006 and April 2018. The patients were divided into FMF positive (CD-FMF) and FMF negative (CD-control) groups. The severity of CD was assessed by the rate of hospitalization because of CD, the need for biological therapy, and whether surgery was performed for CD. RESULTS: Eight (3.8%) of 210 CD patients have concomitant FMF, which is 35 to 40 times higher than expected in an endemic region for FMF. Baseline demographic parameters, location/behavior of the CD, and initial therapeutic regimens were similar between the 2 groups. The prevalence of peripheral arthritis was significantly higher in CD-FMF group (37.5% vs. 10.4%, respectively, P =0.04). A significantly greater proportion of the CD-FMF patients had received biological therapy (50% vs. 11.9%; P =0.012). Steroid dependence and CD-related hospitalization rates in the CD-FMF group were relatively higher but were not statistically significant (37.5% vs. 15.3 and 62.5% vs. 41.1%). CONCLUSIONS: Our findings indicate that the disease course of CD tends to be more severe in patients with coexisting FMF.

Dermatological Comorbidities in Patients with Familiar Mediterranean Fever.

is missing (Short communication).

E148Q variant: a familial Mediterranean fever-causing mutation or a sequence variant?

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease, linked to mutations in the MEFV gene. The p.E148Q variant, found on exon 2, has an uncertain role in FMF, with debates on whether it is a benign polymorphism or a pathogenic mutation. This study aimed to assess the clinical characteristics and severity of FMF in patients homozygous for the p.E148Q variant and to evaluate the impact of the p.V726A variant in these patients. This retrospective cohort study analyzed data from electronic medical records at Carmel Medical Center, Israel. Patients who underwent genetic testing for FMF from November 2004 to December 2019 and had p.E148Q/p.E148Q or p.E148Q/p.E148Q + p.V726A variants were included. Disease severity was assessed using the Tel Hashomer Key to Severity Score. Statistical analyses compared clinical characteristics and severity between genotype groups. The study included 61 FMF patients, with 24 (39%) having p.E148Q/p.E148Q and 37 (61%) having p.E148Q/p.E148Q + p.V726A variants. The majority (72%) were Druze. Most patients (65.5%) exhibited mild disease, while 31.1% had moderate disease, with no cases of severe disease. Colchicine treatment significantly reduced CRP levels in all patients. CONCLUSION: These findings suggest that the p.E148Q variant, whether alone or with p.V726A, generally results in mild to moderate FMF severity, supporting its pathogenic role in particular ethnicity. These results contribute to understanding the clinical significance of the p.E148Q variant and considering the patient's need for Colchicine treatment. WHAT IS KNOWN: • The role of the p.E148Q variant in FMF is debated, with questions about whether it is a benign polymorphism or a pathogenic mutation. • The prevalence of MEFV variants can vary significantly among different ethnic groups. WHAT IS NEW: • The p.E148Q variant has clinical significance in particular ethnicities, as supported by a significant reduction in CRP levels following colchicine treatment. • The p.E148Q variant, whether alone or with p.V726A, generally results in mild to moderate FMF severity.

Is compressed colchicine tablet superior to other colchicine preparations in patients with familial Mediterranean fever?

AIMS: The aim of our study is to evaluate the differences in effectiveness, dosage, and side effect profiles in the use of colchicine preparations and evaluate the superiority of compressed colchicine tablets in familial Mediterranean fever (FMF) patients with resistance or intolerance to coated colchicine tablets. MATERIALS AND METHODS: Patients who were diagnosed with FMF according to the Tel Hashomer criteria, aged 18 years and older, and switched from compressed colchicine to coated colchicine tablets in the rheumatology clinic of Gazi University were identified. The daily colchicine dose and FMF attack frequency before and after switching from coated colchicine tablets to compressed colchicine tablets were compared. RESULTS: The study included 43 female (72.9%) and 16 male patients (27.1%), and the mean age was 34.54 ± 8.3 years. The number of attacks per year was significantly reduced after switching to compressed colchicine tablets, and daily colchicine doses were lower after switching to compressed colchicine tablets (1.97 ± 0.23 vs 1.78 ± 0.39 mg, p < 0.001). CONCLUSION: Compressed colchicine tablets were shown to be superior to other colchicine preparations and compressed colchicine tablets to be a useful treatment option before initiating biological agents in patients who were unresponsive to coated colchicine.

α9ß1 integrin & its ligands as new potential biomarkers in FMF.

Background & objectives Familial Mediterranean Fever (FMF) manifests as a hereditary condition characterized by repeated bouts of fever, abdominal, chest, and joint discomfort, and swelling. Colchicine is the most common form of treatment, but it does not eliminate the disease. The underlying causes of the inflammatory mechanism are still not fully known. Methods A total of 20 healthy controls, 16 individuals with FMF in the attack period, and 14 in the remission period participated in the study. ITGA9, ITGB1, OPN, TNC, VEGF, VCAM-1, TGM2, TSP-1, Emilin-1, and vWF levels were measured by ELISA by obtaining serum from blood samples of individuals. In addition, gene expressions of α9ß1 (ITGA9, ITGB1) and its best known ligands (TNC, SPP1) were analyzed by quantitative real-time PCR (qPCR). Results The findings of this study showed that serum levels of α9ß1 and its ligands were higher in individuals with FMF in the attack period than in the healthy controls and the FMF group in the remission period (P<0.05). The marker levels of the healthy group were also higher than those in the remission period (p<0.05). In addition, when the gene expressions were compared between the healthy controls and FMF group, no significant difference was found for ITGA9, ITGB1, TNC, and SPP1 genes. Interpretation & conclusions The function of α9ß1 and its ligands in FMF disease was investigated for the first time in this study as per our knowledge. Serum levels of these biomarkers may help identify potential new targets for FMF disease diagnosis and treatment approaches.

Clinical presentation and genetic variants in patients with autoinflammatory diseases: results from the German GARROD registry.

To investigate clinical symptoms and genetic variants in patients from the German anti-IL-1 registry for autoinflammatory orphan diseases (GARROD) between 2013 and 2022. Multicentre, retrospective analysis of demographic, clinical and genetic data of patients with autoinflammatory diseases (AID) who received anti-IL-1 targeted therapy. The cohort comprised 152 patients with familial Mediterranean fever (FMF; n = 71), cryopyrin-associated periodic syndromes (CAPS; n = 43), TNF-receptor associated periodic syndrome (TRAPS; n = 19), mevalonate kinase deficiency (MKD; n = 3) and unclassified AID (uAID; n = 16). Inflammatory attacks started in 61.2% of the patients before the age of 18 years. The delay between the first AID attack and anti-IL-1 therapy was 17.8 years. Monogenetic AIDs were diagnosed by clinical symptoms. Genetic analyses confirmed the diagnosis in 87.3% of patients with FMF, 65.2% with CAPS and 94.8% with TRAPS. Among this group, heterozygous MEFV variants and variants of unknown significance (VUS) were detected in 22.5% of patients with FMF, 51.2% with CAPS and 47.4% with TRAPS. Patients with VUS were older at disease onset which is consistent with a milder phenotype. Twenty-four patients had secondary AA amyloidosis (AA) at initiation of anti-IL-1 therapy. The mean age of these patients was 16.4 years at their first attack and 44.9 years at the time of AA diagnosis. Turkish-Armenian ancestry correlated with MEFV variants and higher FMF disease activity compared to German ancestry. Molecular genetic analyses should substantiate the clinical diagnosis of a monogenetic AID. Our data support the concept of variable penetrance of VUS which can be associated with late-onset AID.

Sacroiliitis in familial Mediterranean fever: A rare joint involvement of the disease.

AIM: Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease characterised by recurrent episodes of fever and polyserositis. Sacroiliac joint involvement is rare in FMF patients. The purpose of this study was to evaluate the demographic, clinical, laboratory and imaging findings of patients with FMF who developed sacroiliitis. METHODS: The files of paediatric patients aged 0-18 years who were followed up with a diagnosis of FMF were retrospectively reviewed. FMF patients with evidence of sacroiliitis on magnetic resonance imaging (MRI) were included in the study. RESULTS: Among 1062 FMF patients, 22 (12 males; median age 8.5) (2.1%) of them were found to have sacroiliitis. FMF was diagnosed before sacroiliitis in nine (40.9%) patients and after in 13 (59.1%) patients. The most common symptom in patients with sacroiliitis was low back pain (n = 21, 95.5%). In MEFV gene analysis, M694V was found in 16 (72.7%) patients and was the most common mutation. MRI showed evidence of sacroiliitis in all patients. All patients were using colchicine. Patients with FMF-associated sacroiliitis, remission was achieved with non-steroidal anti-inflammatory drugs in 12 (54.5%), conventional disease-modifying antirheumatic drugs in six (27.3%) and tumour necrosis factor inhibitor treatment in four (31.8%). Four (31.8%) patients experienced sacroiliitis when colchicine incompatible and four (31.8%) patients experienced sacroiliitis while using biologic agents for colchicine-resistant FMF. CONCLUSIONS: FMF-associated sacroiliitis should be considered especially in patients with M694V mutation if they have symptoms such as low back pain. Colchicine-resistant FMF patients should be evaluated for sacroiliitis symptoms at each visit.

Effect of Colchicine Treatment on Clinical Course in Children with PFAPA Syndrome.

INTRODUCTION: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) is the most common periodic fever condition in children. There is no consensus on treatment to prevent attacks and reduce their frequency. In this study, we aimed to evaluate the effectiveness of colchicine treatment in PFAPA syndrome. In addition, we described the demographic and clinical features of PFAPA patients. MATERIALS AND METHODS: We retrospectively analyzed 58 PFAPA patients who were started on colchicine treatment between January 2017 and January 2022. Demographic data, clinical features, laboratory tests, genetic analysis of MEditerranean FeVer (MEFV) mutations, and autoinflammatory disease activity index (AIDAI) scores of all patients were evaluated. In addition, patients were divided into two groups according to MEFV variants and compared. RESULTS: Attack frequency, duration, and AIDAI scores decreased in all patients after colchicine treatment. Duration of follow-up was 13.53±6.65 months. The median±IQR age at diagnosis was 3.2 (2-5) years. Thirty three (56.9%) patients had heterozygous mutations of MEFV. The most common MEFV variants were M694V (63.6%). There was no significant difference between the two groups in terms of colchicine responses. CONCLUSION: Colchicine treatment is effective and safe in patients with PFAPA who have frequent attacks. No association was established between the presence of heterozygous mutations of MEFV and colchicine response.

Anxiety and depression among patients with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever (FMF) is a systemic autoinflammatory disease that requires lifelong treatment and is associated with several comorbidities, including mental health disorders such as anxiety and depression. FMF and mental health necessitate further research; hence, this study aims to observe anxiety and depression and their relationship with several variables in patients with FMF. METHODS: As the study population, 360 FMF patients were surveyed between June and October 2022. Surveys included inventories assessing anxiety and depression, i.e., the Beck's Depression Inventory (BDI), the Beck's Anxiety Inventory (BAI), and the State-Trait Anxiety Inventory (STAI). RESULTS: Mean scores for STAI-Y1 (state), STAI-Y2 (trait), BAI, and BDI were 42.2 ± 12.0, 45.9 ± 10.6, 24.0 ± 13.9, and 13.1 ± 8.99, respectively. Medication-adherent patients had significantly lower scores on STAI-Y1 (41.5 ± 11.4 vs. 45.2 ± 14.0; p-value: 0.04). M694V homozygous patients exhibited significantly lower scores in the BDI (12.4 ± 9.37 vs. 13.2 ± 8.93; p-value: < 0.001) and BAI (17.0 ± 12.1 vs. 25.1 ± 13.9; p-value: 0.001). The patients with an exon-10 mutation demonstrated significantly lower scores compared to patients with an exon­2 mutation (17.9 ± 12.3, 29.6 ± 13.3; p-value: < 0.001). CONCLUSION: The patients with FMF had mild depression and moderate anxiety scores. A higher level of education and medication adherence were associated with lower levels of anxiety. Likewise, the patients with genotypes associated with severe disease courses had lower levels of anxiety. We suggest that physicians should be more attentive to patients with a milder disease course and ensure that these patients are provided with sufficient treatment and knowledge about their disease.

Clinical Associations of E148Q Heterozygosity: What to Expect From E148Q?

OBJECTIVE: The exact effects of MEFV variants on inflammation are still under investigation, and reports on variants of unknown significance, particularly the E148Q variant, have been conflicting. Therefore, this study aims to investigate patients exhibiting E148Q heterozygosity, focusing on diagnoses and disease courses to assist physicians in interpreting the variant. METHODS: Data of pediatric patients presenting to the Pediatric Rheumatology clinic between November 2016 and September 2023, exhibiting only E148Q heterozygosity in MEFV gene analysis, were extracted. Patients who were lost before 9 months of follow-up have been excluded to ensure the completion of initial diagnostic tests and evaluations. RESULTS: Among the 119 patients with E148Q variant, the diagnoses were as follows: healthy, 51.3%; IgA vasculitis, 10.1%; Familial Mediterranean Fever (FMF), 7.6%; Periodic fever, Aphtous stomatitis, Pharyngitis, Adenitis (PFAPA), 6.7%; and other diagnoses, 19.3%. IgA vasculitis patients experienced articular, gastrointestinal, and renal involvement at rates of 91.7%, 58.3%, and 16.7%, respectively. Complete response, partial response, and no response to colchicine were 37.5%, 12.5%, and 50%, respectively, in PFAPA patients. All FMF patients responded to colchicine treatment resulting in reduced mean FMF episode counts in 6 months from 3.22 ± 0.92 to 0.56 ± 0.52. CONCLUSIONS: The E148Q variant may amplify inflammation and modify disease courses. Patients with the E148Q variant experiencing typical FMF episodes should receive colchicine, but clinicians should exercise caution regarding alternative diagnoses. Additionally, the E148Q variant may increase acute phase reactants and disease severity in IgA vasculitis. However, to reach definitive conclusions on its treatment-modifying role in PFAPA, universal diagnosis and treatment response criteria should be adopted.

Factors Associated With Successful Withdrawal of Biologic Agents in Children With Colchicine-Resistant Familial Mediterranean Fever.

BACKGROUND: Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease, and colchicine is the mainstay of treatment. Approximately 5%-10% of patients may respond inadequately to colchicine, and anti-interleukin-1 (anti-IL-1) agents are important treatment options in these patients. The aim of this study was to see whether there is any factor associated with the withdrawal of these anti-IL-1 agents and to investigate the characteristics of colchicine-resistant FMF patients who needed biological therapy. METHODS: Demographic, clinical characteristics, and disease severity of patients, at 2 referral centers, between 2012 and 2022, in whom anti-IL-1 treatment was continued and discontinued, were compared in this study. The international severity scoring system for FMF (ISSF) was used for disease severity assessment. RESULTS: In 64 colchicine-resistant FMF patients, the median (interquartile range) duration of biological treatment was 39 (45) months. Treatment of 26 patients (40.6%) was started with anakinra and 38 (59.4%) with canakinumab. During follow-up, anti-IL-1 treatment was discontinued in 23 patients (35.9%). High ISSF scores before biological treatment, presence of exertional leg pain, subclinical inflammation, and comorbidities were found to be statistically more frequent in the group whose biological therapy could not be discontinued ( p = 0.009, p = 0.006, p = 0.026, p = 0.001, respectively). CONCLUSIONS: Low ISSF scores before biological treatment with no accompanying exertional leg pain, subclinical inflammation, and comorbidities may be stated as an associated factors in terms of the discontinuation of biological agents in colchicine-resistant pediatric FMF patients.

Protracted Febrile Myalgia Syndrome: A Rare and Difficult Manifestation of Familial Mediterranean Fever.

OBJECTIVE: Protracted febrile myalgia syndrome (PFMS) is characterized by severe myalgia, fever, abdominal pain, and arthralgia/arthritis episodes lasting for several weeks in patients with familial Mediterranean fever. Treatment options include nonsteroidal anti-inflammatory drugs, corticosteroids, and anti-interleukin-1 therapy. This study aimed to share our experiences of PFMS so as to shed light on this rare and elusive condition. METHODS: This cross-sectional analysis included 17 patients diagnosed with PFMS at our pediatric rheumatology clinic between January 2018 and September 2023. RESULTS: In our clinic, 17 (1%) of 1663 familial Mediterranean fever patients presented with PFMS, and it was the initial manifestation in 10 patients (58.8%) in the cohort. Eight of the 17 patients had an M694V homozygous mutation in the MEFV gene. A magnetic resonance imaging showed myositis and fasciitis in just 1 patient, and myositis alone was evident in 5 others. Symptoms improved in 2 patients with nonsteroidal anti-inflammatory drugs, whereas prednisolone improved symptoms in 12 patients and anakinra was required in 3 patients. Patients who received anakinra had another severe attack and required long-term anakinra or canakinumab. CONCLUSIONS: Syndrome for PFMS is difficult to recognize as it can sometimes be the first manifestation of familial Mediterranean fever. The syndrome is not accompanied by fever in some patients, even though the word febrile is part of its name. Most patients respond dramatically to nonsteroidal anti-inflammatory drugs or corticosteroids. In some patients with PFMS, long-term anakinra or canakinumab treatment may be more useful in preventing severe attacks of PFMS than short-term (5 to 7 days) anakinra treatment.